Prostate cancer staging

Prostate cancer is second only to lung cancer as a cause of cancer-related mortality, and early diagnosis is essential for improving survival. The three tests commonly used to detect prostate cancer are the digital rectal exam (DRE), transurethral ultrasound (TRUS), and monitoring serum prostate specific antigen (PSA) levels.

The American Cancer Society reports that in 1997, prostate cancer was diagnosed in over 200,000 men, and caused an estimated 40,000 deaths.[1] Today, prostate cancer is the most commonly diagnosed type of cancer among men, and it also accounts for over one-third of newly diagnosed cancers in American men and 13% of cancer-associated deaths.[1] Prostate cancer is second only to lung cancer as a cause of cancer-related mortality.[1]

Prostate cancer affects mostly older men; diagnosis before age 40 years is rare, and the median age at diagnosis is 70 years.[2] Data from a study sponsored by the National Cancer Institute involving patients from nine U.S. cancer centers indicated that the incidence of prostate cancer increased 6.4% per year on average among Caucasian males ages 59 to 79 years.[2] The greatest increase (7.7%) was in men ages 60 to 69 years. Results from this study also revealed a substantial increase in prostate cancer (from 276 per 100,000 men to 383 per 100,000 men) between 1983 and 1989. The spurt is probably due to the increased use of screening tests, including measurement of serum prostate specific antigen (PSA) and the digital rectal exam (DRE); an increased awareness of the disease in the population; and the fact that more men are living longer.

Expression of prostate cancer varies, and it is often undetected. Some autopsy studies have shown that nearly 30% of men older than age 50 years have evidence of malignancy in the prostate gland, with no clinical evidence of the disease.[2] When detected at autopsy, the latent cancer may be only a microscopic lesion that never became symptomatic during a person's lifetime. On the other hand, a clinically significant tumor may be found that could decrease the patient's life span if treatment had not been initiated at once. The incidence of autopsy-detected prostate cancer, of whatever nature, increases to over 40% in men older than age 75 years, and the incidence approaches 100% in men ages 90 years and older.[2] For a 50-year-old man, the estimated lifetime risk of prostate cancer is 42%, the risk of clinical disease is 9.5%, and the risk of death from the disease is 2.9%.[2]

Etiology, signs, and symptoms of prostate cancer

The cause of prostate cancer is unknown. Several risk factors have been suggested, including too little dietary fiber, too much dietary fat, and too much (or too little) Vitamin A.[3] Heredity seems to be important; the likelihood of prostate cancer in a man with a father or brother who has the disease is twice as great (16% vs. 8%) when compared with a man with a no family history of the disease.[3] In the United States, prostate cancer is more common among African-Americans than Caucasians and is least common within the Asian-American population.[3] However, Japanese men experience an increased incidence if they move to the United States.[3] The incidence of prostate cancer also seems to be greater among printers, painters, rubber workers, loggers, ship fitters, farmers, and drag and chemical workers.[3] However, other than family history, most of the data on risk factors are conflicting or inconclusive.[3]

Most patients are asymptomatic at the time of diagnosis. If symptoms are present, they may be confused with those that accompany benign prostatic hyperplasia (BPH). These symptoms include pain with urination, increased frequency of urination, hematuria, a decline in the force of the urinary stream, dribbling, incomplete emptying of the bladder, and nocturia.[4] Consequently, screening tests that can identify men with possible prostate cancer are essential. Three tests commonly used for this purpose include DRE, transurethral ultrasound (TRUS), and serum PSA levels.

Characteristics of PSA

Prostate-specific antigen is a glycoprotein weighing approximately 33 to 34 kDa. Structurally, PSA is similar to other proteases, with disulfide bonds (five for PSA) that help produce a three-dimensional configuration for the molecule's active site. In several reports, the half-life for PSA varies from 1.9 to 4.6 days.[5]

As a member of the kallikrein family of neutral proteases that includes kallikrein I, PSA has 50-80% homology with other proteases.[5-7] PSA is one of several proteolytic enzymes that causes liquefaction of semen immediately following ejaculation. PSA is produced by the epithelial cells of the prostate, and is present in seminal fluid, serum, and urine. Recent studies have also found PSA in periurethral tissue and parotid glands.[8] (See Table 1.)

In serum, PSA exists in several free and complexed forms, with at least four isotypes [ILLUSTRATION OMITTED]. In healthy men, approximately 80% of PSA is complexed or bound to one of three protease inhibitors, primarily with [[Alpha].sub.1]-antichymotrypsin (ACT), but also with [[Alpha].sub.1]-antitrypsin ([A.sub.1]A), or [[Alpha].sub.2]-macroglobulin ([A.sub.2]M). Approximately 20% of PSA circulates as free (f)PSA.

Measurement of serum PSA

Various commercial procedures detect total PSA by sandwiching PSA between two antibodies. The first antibody is directed at and captures one site (epitope) on the PSA molecule in the serum sample. A second antibody molecule, tagged with an enzyme or other marker, binds to a second site on the PSA molecule to complete the sandwich. Signal measurement for this type of assay is directly proportional to the concentration of PSA in the sample.

Unresolved analytical issues[9-12] are inherent in this approach for detecting PSA:

* Different commercial assays use different mono- or polyclonal antibodies, which can yield different results (see Table 2).

* Different sources of calibrators can be mixtures of complexed and free PSA, which cause variations between methods.

* More than one form of PSA is present in the serum. In the range from approximately 4 ng/mL to 10 ng/mL, it is especially important for the assay to measure equally any form of complexed and fPSA. Such an assay could be termed equimolar, indicating that the assay antibodies will combine with a site on the PSA molecule, regardless of whether the PSA was originally complexed in the serum.

* Results from a recent survey suggest that equimolar binding does not occur in all assays (see Table 2).[9-11] Striking differences exist between methods; variations of more than 50% can occur within an assay. This latter point must be considered when monitoring a patient who is either being treated for prostate cancer or being followed, but not yet treated.

All of these analytical issues must be considered when interpreting data from different laboratories and when interpreting derivative assays such as PSA density and PSA velocity (described below). Most authors consider PSA to be the most sensitive marker of prostate cancer, and most laboratories have replaced the assay of prostate acid phosphatase (PAP) with PSA to screen for and monitor prostate cancer. However, PSA is not specific for prostate cancer and may be increased by many prostatic diseases, manipulations, or other conditions (see Table 1).

Detection of prostate cancer: Which tests to use?

Of the three commonly used tests for prostate cancer (DRE, TRUS, and serum PSA levels), the positive predictive values (PPV) are 22% to 36% for DRE, 15% to 41% for TRUS, and 22% to 35% for PSA levels greater than 4.0 ng/mL, but 65% to 67% for PSA levels greater than 10.0 ng/mL.[13-15] When both the DRE and the TRUS are abnormal, the PPV is 37% to 61%.[13-15] Combining the PSA and TRUS yields a PPV of 33% to 52%.[13-15]

When all three tests are abnormal, use of this combination yields the best PPV (62% to 74%).[13-15] However, the data for all three tests are only somewhat better than using just the DRE and PSA (69% for levels greater than 10.0 ng/mL), and the use of all three tests markedly increases the cost of screening.[2] Therefore, if the PPV could be increased for results obtained when using just the DRE and PSA (or some other cost-effective method), use of the TRUS could be minimized while improving patient care and reducing costs. It is recommended that DRE and PSA be used as initial screening tests.[4,13-15]

Attempts to improve the diagnostic value of PSA results Age-specific reference intervals.

Normally, as a man ages the prostate enlarges and produces more PSA. Therefore, age-specific normal ranges (see Table 3) have been suggested as a more useful aid to detect prostate cancer than the 0 to 4 ng/mL previously considered normal, regardless of a man's age.[16]

Use of age-specific normal ranges has several advantages:

* It can account for the continued enlargement of the prostate.